EP3212613A1 - (z)-3,4,5-trimethoxystyrylbenzenesulfonamides as potential anticancer agents - Google Patents

(z)-3,4,5-trimethoxystyrylbenzenesulfonamides as potential anticancer agents

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Publication number
EP3212613A1
EP3212613A1 EP15808035.8A EP15808035A EP3212613A1 EP 3212613 A1 EP3212613 A1 EP 3212613A1 EP 15808035 A EP15808035 A EP 15808035A EP 3212613 A1 EP3212613 A1 EP 3212613A1
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Prior art keywords
trimethoxystyryl
cell lines
compound
compounds
cancer
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EP15808035.8A
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German (de)
French (fr)
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EP3212613B1 (en
Inventor
Ahmed Kamal
Mahesh RASALA
Challa RATNA REDDY
Gajjela BHARATH KUMAR
Visweswara SASTRY
Anver BASHA SHAIK
Vangala SANTHOSH REDDY
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Council of Scientific and Industrial Research CSIR
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C07C311/38—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton
    • C07C311/44—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring

Definitions

  • the present invention relates to (Z)-3,4,5-trimethoxystyrylbenzenesulfonamides as potential anticancer agents.
  • the present invention relates to the synthesis and biological evaluation of novel (Z)-3,4,5-trimethoxystyrylbenzenesulfonamides of general formula A as potential anticancer agents and a process for the preparation thereof.
  • Microtubules are protein polymers that are involved in many physiological processes, especially mitosis and cell division, and are formed by a-tubulin and ⁇ -tubulin heterodimers. Microtubules are essential for maintaining cell shape and polarity, the intracellular transport of vesicles and organelles. During eukaryotic cell division, microtubules form mitotic spindles, which align replicated chromosomes to the equatorial plane and mediate the subsequent segregation of chromosomes to the two daughter cells [K. H. Downing, E. Nogales, Curr. Opin. Cell Biol. 1998, 10, 16- 22].
  • CA-4 Combretastatin A-4 SI is a natural cis-stilbene that was isolated by Pettit co workars in 1989 from the South African willow tree Combretumcaffrum. Because of its structural simplicity and strong anticancer properties, CA-4 is presently one of the most promising target to develop new potential drugs for cancer.
  • CA-4 has been found to be a potent inhibitor of tubulin polymerization,as it binds to the colchicine binding site and exerts significant cytotoxicity toward a wide range of human cancer cell lines, including multidrug-resistant cancer cellsG. R. Pettit, M. R. Rhodes,D.L. Herald, E. Hamel, J. M. Schmidt, R. K. Pettit, J. Med. Chem. 2005, 48, 4087 -4099].
  • E7010 (N- [2-[(4-hydroxyphenyl)amino]-3-pyridinyl]-4-methoxybenzenesulfonamide) S4 an orally active sulfonamide antitumor agent that is currently in a Phase I clinical trial, showed rather consistent growth-inhibitory activities against a panel of different human tumor cell lines. It also showed a dose-dependent inhibition of tubulin polymerization, which correlated well with the cell growth- inhibitory activity. 14C -labeled E7010 bound to purified tubulin, and this binding was inhibited by colchicine but not by VCR. However, its binding properties were different from those of colchicine, as well as those of VCR.
  • E7010 was active against two kinds of VCR -resistant P388 cell lines, one of which showed multidrug resistance due to the overexpression of P-glycoprotein (resistant to Taxol), and the other did not show multidrug resistance (sensitive to Taxol). Furthermore, E7010 is a tubulin-binding agent that has a wider antitumor spectrum than VCR and has different properties from those of VCR or Taxol [Yoshino, Hiroshi; Ueda, Norihiro; Niijima, Jun; Sug - 2497] .
  • the main objective of the present invention to provide (Z)-3,4,5-trimethoxystyryl benzene sulfonamides useful as potential anticancer agents.
  • Yet another objective of the present invention is to provide a process for the preparation of (Z)-3,4,5-trimethoxystyryl benzene sulfonamides.
  • the present invention provides a(Z)-3,4,5-trimethoxystyrylbenzene sulfonamides of general
  • the present invention further provides a process for preparation of (Z)-3,4,5- trimethoxystyryl benzene sulfonamides of formula 9a-9y, lOa-lOy, lla-lly, 12a-12y, 13a- 13y, 14a-14y, 15a-15y, 16a-16y, 17a-17y, 18a-18y, 19a-19y, 20a-20y, 21a-21y, 22a-22y and 23a-23y
  • the present invention provides the process for preparation of compounds of general formulae A
  • the obtained witting salt was reacted with substituted benzaldehydes (5a-5o) in presence of NaH in CH 2 CI 2 to produce (Z)-l,2,3-trimethoxy-5-(substituted-nitrostyryl)benzene 6(a-o) and (E)- 1,2,3 -trimethoxy-5- (substituted-nitrostyryl)benzene in (1: 1)% of yield.
  • Z)-l,2,3-trimethoxy-5-(substituted nitrostyryl)benzene reduced with Zn ammoniumformate in methanol produced (Z)-3-(3,4,5- trimethoxystyryl)aniline.
  • the present invention relates to the compounds, synthesis and biological evaluation of novel (Z)-3,4,5-trimethoxystyryl benzene sulfonamide derivatives of general formula A as potential anticancer agents and a process for the preparation thereof
  • R H, CI, F, Br, OCH 3 , NH 2 , N0 2 , OH
  • [026]/n vitro cytotoxicity The (Z)-3,4,5-trimethoxystyryl benzene sulfonamides (13a,13c,17a,17c and 12a) have been tested against sixty human tumor cell lines derived from different type of nine cancer cell lines (leukemia, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer and breast cancer) as per the NCI protocol. For each compound, dose response curves for individual cell lines have been measured at a minimum of five concentrations at 10 fold dilutions.
  • GI 50 concentration for50% cell growth inhibition
  • TGI total cell growth inhibition
  • LC 50 50% cell death
  • the compounds 13a,13c,17a,17c and 12a has been evaluated for their in vitro cytotoxicity in sixty cell lines from nine human cancer types of leukemia (K-562, SR), lung (Hop-62, NCI-H226, NCI-H522), colon (HCT-116, HCT- 15, HCC-2998), CNS (SF-539), melanoma (SK-MEL-5, UACC-62, M14), ovarian (IGROV1), renal (A498), prostate (PC3) breast (BT-549, MDA-MB-435, HS578T)origin. The results are expressed as percent of cell growth determined relative to that of untreated control cells (Table 2). The representative compounds 13a, 13c, 17a, 17c and 12a showed significant cytotoxicity against almost 50 above cancer cell lines.
  • the compounds 17a,17c,13a,13c and 12a exhibited a wide spectrum of activity against fifty six cell lines in nine different types of cancer cell lines, most of the compounds with GI 50 value range of 18-50nM. Particularly, the compounds 13a, 17a, and 12a were more potent than the compoundsl3candl7cagainst all the tested cell lines.
  • 17c and 12a also shows good GI 50 values below 30nm around eight tumor cell lines, with GI 50 values below 50nm shows by thirty above cell lines.
  • the growth of NCI-H522 cell line were affected by compound 17awith GI 50 values as 20.2nM.
  • the colon cancer cell line colo-205 affected by compound 13a with GI 50 value of 21.4 nM.
  • the GI 50 values for compounds 17a, 17c, 13a and 12a againstrenal A498 cell line were 18.8, 22.9, 21.7 and 35.3 nM respectively.
  • the cell lines CCRF-CEM, HL-60(TB),SR and K-562 were affected by 17a with GI 50 value 30.1, 23.5,31.9 and 28.6 nM and 13a with GI 50 values 32.9,23.4,35.2 and 27.2 respectively, and
  • the GI 50 values for compounds 17a,17c and 13a againstmelanoma MDA-MB-435 cell line were 19.0,22.2 and 21.1 nM, respectively.
  • the cell lines SF-295,SF-539,U251 and SNB75 were affected by 17a with GI 50 values 33.9, 29.3,37.4 and 25.5 nM and 13a with GI 50 values 31.1,25.3,35.7 and 26.5 respectively, the GI 50 values for the compound 12a against melanoma cancer cell line MDA- MB-435is 27.4 nM.
  • the growth of HOP-62 and NCI- H522 cell lines were affected by compound 12awith GI 50 values as 41 and 20.4 nM, respectively.
  • the growth was affected by 12a with GI 50 value 42.6 nM.
  • the GI 50 values for the compounds 17a, 13a and 12a against Non- small cell lungcancer cell line NCI-H522 is 20.2,19.7 and 20.4nM respectively.
  • the GI 50 values for compounds 17a,17c,13a and 12aagainst melanoma cell line MDA-MB-435 were 19.2,22.2,21.1 and 27.4 nM respectively.
  • the GI 50 values for the compound 12aagainst renal cancer cell line A498 were 35.3nM.
  • the growth affected by the compounds 17a, 17c, 13a and 12a against all the cancer cell lines with GI 50 values range 18-50 nM.
  • NT NotTested.
  • Log 10 GI 50 , Log 10 TGI and Log 10 LC 50 mean graphs mid points(MG_MID) of in vitro cytotoxicity data for the compoundl7a,17c,13a,13c and 12a against human tumor cell lines.
  • the present invention provides new (Z)-3,4,5-trimethoxystyrylbenzenesulfonamides that may be useful as antitumor agents.

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Abstract

(Z)-3,4,5-Trimethoxystyrylbenzenesulfonamides as potential anticancer agents [Formula should be inserted here] The present invention relates to a compound of general formula A.The invention provides the synthesis of (Z)-3,4,5-trimethoxystyrylbenzenesulfonamides useful as potential antitumor agents against human cancer cell lines and a process for the preparation thereof.

Description

(Z)-3,4,5-TRIMETHOXYSTYRYLBENZENESULFONAMIDES AS
POTENTIAL ANTICANCER AGENTS FIELD OF THE INVENTION
[001] The present invention relates to (Z)-3,4,5-trimethoxystyrylbenzenesulfonamides as potential anticancer agents. The present invention relates to the synthesis and biological evaluation of novel (Z)-3,4,5-trimethoxystyrylbenzenesulfonamides of general formula A as potential anticancer agents and a process for the preparation thereof.
BACKGROUND AND PRIOR ART SEARCH OF THE INVENTION
[002] Microtubules are protein polymers that are involved in many physiological processes, especially mitosis and cell division, and are formed by a-tubulin and β-tubulin heterodimers. Microtubules are essential for maintaining cell shape and polarity, the intracellular transport of vesicles and organelles. During eukaryotic cell division, microtubules form mitotic spindles, which align replicated chromosomes to the equatorial plane and mediate the subsequent segregation of chromosomes to the two daughter cells [K. H. Downing, E. Nogales, Curr. Opin. Cell Biol. 1998, 10, 16- 22]. These drugs interfere with the polymerization depolymerization properties of microtubules to prevent cell cycle progression, inducing the cells to undergo programmed cell death. Due to this microtubules are potential targets for the development of chemotherapeutic drugs which target rapidly dividing cancer cells [S. Honore, E. Pasquier, D. Braguer, Cell Mol. Life Sci. 2005, 62, 3039 -3056].Combretastatin A-4 (CA-4) SI is a natural cis-stilbene that was isolated by Pettit co workars in 1989 from the South African willow tree Combretumcaffrum. Because of its structural simplicity and strong anticancer properties, CA-4 is presently one of the most promising target to develop new potential drugs for cancer. CA-4 has been found to be a potent inhibitor of tubulin polymerization,as it binds to the colchicine binding site and exerts significant cytotoxicity toward a wide range of human cancer cell lines, including multidrug-resistant cancer cellsG. R. Pettit, M. R. Rhodes,D.L. Herald, E. Hamel, J. M. Schmidt, R. K. Pettit, J. Med. Chem. 2005, 48, 4087 -4099]. Recently it has been reported that a new class of combretastatins such as (Z)-5-(3,5-dimethoxystyryl)-2-methoxyaniline S3 exhibit potential cell proliferation against CA-4 resistant cell lines (BMEC and HT-29) and also explained that in these (Z)-5-(3,5-dimethoxystyryl)-2-methoxyaniline inhibited tubulin polymerization five times stronger than CA-4 by binding at colchicine binding site. (Simoni D, Romagnoli R, Baruchello R, Rondanin R, Grisolia G, Eleopra M, Rizzi M, Tolomeo M, Giannini G, Alloatti D, Castorina M, Marcellini M, Pisano C, Novel A-ring and B-ring modified combretastatin A-4 (CA-4) analogues endowed with interesting cytotoxic activity, /. Med. Chem.2008, 51, (19), 6211-6215). E7010 (N- [2-[(4-hydroxyphenyl)amino]-3-pyridinyl]-4-methoxybenzenesulfonamide) S4 an orally active sulfonamide antitumor agent that is currently in a Phase I clinical trial, showed rather consistent growth-inhibitory activities against a panel of different human tumor cell lines. It also showed a dose-dependent inhibition of tubulin polymerization, which correlated well with the cell growth- inhibitory activity. 14C -labeled E7010 bound to purified tubulin, and this binding was inhibited by colchicine but not by VCR. However, its binding properties were different from those of colchicine, as well as those of VCR. E7010 was active against two kinds of VCR -resistant P388 cell lines, one of which showed multidrug resistance due to the overexpression of P-glycoprotein (resistant to Taxol), and the other did not show multidrug resistance (sensitive to Taxol). Furthermore, E7010 is a tubulin-binding agent that has a wider antitumor spectrum than VCR and has different properties from those of VCR or Taxol [Yoshino, Hiroshi; Ueda, Norihiro; Niijima, Jun; Sug - 2497] .
[003] In continuation of these efforts and our interest in the structural modifications of the combretastatin A4 and E7010, we describe here in an efficient access to the construction of some new (Z)-3,4,5-trimethoxystyryl benzene sulfonamides with improved cytotoxic activity in certain cell lines.
OBJECTIVES OF THE INVENTION
[004] The main objective of the present invention to provide (Z)-3,4,5-trimethoxystyryl benzene sulfonamides useful as potential anticancer agents. [005] Yet another objective of the present invention is to provide a process for the preparation of (Z)-3,4,5-trimethoxystyryl benzene sulfonamides.
[006] Further objective of the present invention is to provide (Z) 3,4,5-trimethoxystyryl benzene sulfonamides of general formula A as promising tubulin polymerization inhibitors. SUMMARY OF THE INVENTION
[007] Accordingly, the present invention provides a(Z)-3,4,5-trimethoxystyrylbenzene sulfonamides of general
wherein, X= H, F, OCH3,OH; R = H, CI, F, OCH3, NH2, N02,OH
[008] In an embodiment of the present invention (Z)-3,4,5-trimethoxystyryl benzene sulfonamides of general formulae A is represented by the compounds of general formulae
wherein
[009]In yet another embodiment the (Z)-trimethoxystyryl)phenyl)benzenesulfonamide are represented by the following compounds:
[009] The present invention further provides a process for preparation of (Z)-3,4,5- trimethoxystyryl benzene sulfonamides of formula 9a-9y, lOa-lOy, lla-lly, 12a-12y, 13a- 13y, 14a-14y, 15a-15y, 16a-16y, 17a-17y, 18a-18y, 19a-19y, 20a-20y, 21a-21y, 22a-22y and 23a-23y
comprising the steps of reacting (Z)-3-(3,4,5-trimethoxystyryl)aniline of formula 7(a-o) with benzenesulfonylchlorides of formulae (a-y) to produce following the compounds (9a-9y to 23a-23y) in solvent pyridine at 0 °C to room temperature for a period of about 2-3 h. After quenching with 2N HCl and addition of appropriate amount of ethyl acetate to the reaction mixture is then extracted the organic layer dried over under reduced pressure resulted to obtain crude products. These crude products were purified by column chromatography using ethyl acetate and hexane solvent system to produce the desired products of formulae 9a-9y, 10a- lOy, lla-lly, 12a-12y, 13a-13y, 14a-14y, 15a-15y, 16a-16y, 17a-17y, 18a-18y, 19a-19y, 20a-20y, 21a-21y, 22a-22y and 23a-23y respectively
wherein, X= H, F, OCH3, OH; R = H, CI, F, OCH3, NH2, N02,OH
In an embodiment of the invention wherein the compound of general formula A are useful as antitumor agents.
In another embodiment of the invention wherein the compound of general formula A have antitumour activity against cell lines selected from the group of non-small cell lung cancer, colon cancer, cervical carcinoma and breast cancer)
In another embodiment, the present invention provides the process for preparation of compounds of general formulae A
wherein the said process comprising;
a)reacting (Z)-3-(3,4,5 trimethoxystyryl)aniline of formula 7(a-o)
with a compound selected from a group consisting of formulae a, b, c, d, f, g, h, I, j, k, 1, m, n, 10 p, q, r, s, t, u, v, w, x and y.
in pyridine at a temperature ranging between 0 to 33 °C for a period of about 2-3 h to obtain a reaction mixture,
(b) adding HC1 and appropriate amount of ethyl acetate to the reaction mixture to obtain an organic layer;
(c) extracting the organic layer followed by drying under reduced pressure to obtain crude products,
(d) purifying the crude product by column chromatography using ethyl acetate and hexane solvent system to obtain the desired products of formulae 9a-9y, lOa-lOy, lla-lly, 12a-12y, 13a-13y, 14a-14y, 15a-15y, 16a-16y, 17a-17y, 18a-18y, 19a-19y, 20a-20y, 21a-21y, 22a- 22yand 23a-y.
DETAILED DESCRIPTION OF THE INVENTION
[010] The precursors (Z)-3-(3,4,5-trimethoxystyryl)anilineof formula 7(a-o) have been preparedusing literature method (Keith A. Monk,a Rogelio Siles,aMallinath B. Hadimani,aBenon E. ugabe,a J. Freeland Ackley,a Scott W. Studerus,a Klaus Edvardsen,b Mary Lynn Trawick,aCharles M. Garner,a Monte R. Rhodes,c George R. Pettitc and Kevin G. Pinneya,*, Bioorganic & Medicinal Chemistry 14 (2006) 3231-3244).The crucial intermediates for the preparation of precursors (Z)-3-(3,4,5-trimethoxystyryl)aniline formula 7(a-o) are (Z)- l,2,3-trimethoxy-5-(3-nitrostyryl)benzene 6(a-o) have been prepared using literature methods ( Kevin G. Pinney,a,* Maria P. Mejia,a Victor M. Villalobos,a Brent E. Rosenquist,a George R. Pettit,b Pascal Verdier-Pinardc and Ernest Hamelc, Bioorganic & Medicinal Chemistry 8 (2000) 2417±2425).
[011]These new 3,4,5-trimethoxystyrylaryl sulfonamide derivatives have shown promising anticancer activity in various cancer cell lines. The molecules synthesized are of immense biological significance. This resulted in design and synthesis of new congeners as illustrated in schemel which comprise: The reaction between (Z)-3-(3,4,5-trimethoxystyryl)aniline of formula 7(a-o) and the benzene sulfonyl chlorides compounds of formulae a to y for the compounds (9a-9y to 23a-23y).
1. Stirring the amines at 0°c and add benzenesulfonylchlorides slowly to the reaction mixture, maintain for 2-3 h at room temperature to obtain the compounds (9a-y to 23a-23y) respectively.
2. Synthesis of (Z) - 3,4,5-trimethoxystyryl benzenesulfonamides.
3. Purified by the column chromatography using different solvents like ethyl acetate and hexane
4. The final step has been carried out by the (Z)-3-(3,4,5-trimethoxystyryl)aniline of formula 7(a-o) and substituted benzene sulfonyl chlorides in pyridine at 0°C. The compounds of formulae a to y for the compounds (9a-9y to 23a-23y)
[012]The key intermediates 3-substituted (Z)-3-(3,4,5-trimethoxystyryl)aniline 7(a-o) are prepared in five sequential steps. 3,4,5-Trimethoxybenzaldehyde (1) reduces with sodiumborohydride in methanol gives (3,4,5-trimethoxyphenyl)methanol (2). This was further reacted with PBr3 in CH2CI2 to produce 5-(bromomethyl)-l,2,3-trimethoxybenzene (3), then this was further reacted with triphenylphosphine in toluene to give 3,4,5-tri- methoxybenzyltriphenylphosphonium bromide (4) in good yields. The obtained witting salt was reacted with substituted benzaldehydes (5a-5o) in presence of NaH in CH2CI2 to produce (Z)-l,2,3-trimethoxy-5-(substituted-nitrostyryl)benzene 6(a-o) and (E)- 1,2,3 -trimethoxy-5- (substituted-nitrostyryl)benzene in (1: 1)% of yield. Z)-l,2,3-trimethoxy-5-(substituted nitrostyryl)benzene reduced with Zn ammoniumformate in methanol produced (Z)-3-(3,4,5- trimethoxystyryl)aniline.
Scheme 1
[013]Reagents and conditions: (i) NaBH4, MeOH, 3 h, 15-20JC (95%) (ii) PBr3, CH2C12> 2 h, 15-20 °C(90%) (iii) PPh3, toluene, 12 h, 80 °C (80%) (iv)NaH, CH2C12, 18 h, 15-20 °C (65%) (v) Zn, HCOONH4, 3 h, 30-40°C, 70%; (vi)Pyridine, 0 °C - RT, 2 h (90%).
[014]The present invention relates to the compounds, synthesis and biological evaluation of novel (Z)-3,4,5-trimethoxystyryl benzene sulfonamide derivatives of general formula A as potential anticancer agents and a process for the preparation thereof
wherein, X= H, F, OCH3, NH2,OH; R = H, CI, F, OCH3, NH2, N02,OH
[015]More particularly the present invention relates to the following compounds:
(Z)-N-(4,5-dimethoxy-2-(3,4,5-trimethoxystyryl)phenyl)-4-hydroxybenzenesulfonamide (23w) (Z)-N-(4,5-dimethoxy-2-(3,4,5-trimethoxystyryl)phenyl)-3,4-difluorobenzenesulfonamide (23x)
(Z)-3-chloro-N-(4,5-dimethoxy-2-(3,4,5-trimethoxystyryl)phenyl)-4- methoxybenzenesulfonamide (23y).
wherein R = H, CI, F, Br, OCH3, NH2, N02, OH
The following examples are given by way of illustration and therefore should not be construed to limit the scope of the present invention.
EXAMPLES
[016] Example 1:
(Z)-4-methoxy-N-(2-methoxy-5-(3,4,5-trimethoxystyryl)phenyl)benzenesulfonamide (12a): To a solution of (Z)-4-methoxy-N-(2-methoxy-5-(3,4,5-trimethoxystyryl) aniline(100 mg, 0.317 rnmol) in a 1:4 mixture of pyridine and anhydrous CH2C12 (10 mL), benzenesulfonylchloride (79 mg,0.380 mmol) was slowly added at 0°C. After 5 min stirring remove ice both and stirred at room temperature 3 h, then the reaction mixture was evaporated to dryness in vacuum and the residue was taken up with CH2CI2 (10 mL). The organic solution was washed with water, 10% aqueous HCl, water and brine, dried over MgS04, and concentrated in vacuum to give 161 mg (90%) of analytically pure compound obtained from a 3: 1 mixture of hexane and ethyl acetate.
1H NMR (CDCI3, 300 MHz) δ (ppm): 3.64 (s, 6H), 3.66 (s, 3H), 3.81 (s, 3H), 3.83 (s, 3H) 6.43 (s, 2H), 6.45 (s, 2H), 6.58 (s, 2H), 6.61 (d, / = 8.5 Hz, 1H), 6.83(d, / = 9.1 Hz, 2H), 6.92-6.96 (m, 2H), 7.42 (d, / = 1.8, NH), 7.61 (d, / = 8.87 Hz, 2H); FAB MAS: (M+H)=485.
Example 2:
[017](Z)-3,4-dimethoxy-N-(2-methoxy-5-(3,4,5-trimethoxystyryl)phenyl)benzenesulfonamide (12b):
To a solution of (Z)-4-methoxy-N-(2-methoxy-5-(3,4,5-trimethoxystyryl) aniline(100 mg, 0.317 mmol) in a 1:4 mixture of pyridine and anhydrous CH2CI2 (lOmL), 4-methoxy benzenesulfonyl chloride (91mg 0.380 mmol) was slowly added at 0 °C. After 5 min stirring remove ice both and stirred at room temperature 2-3 h, then the reaction mixture was evaporated to dryness in vacuum and the residue was taken up with CH2CI2 (10 mL). The organic solution was washed with water, 10% aqueous HCl, water and brine, dried over MgS04, and concentrated in vacuum to give 170 mg (90%) of analytically pure compound obtained from a 3: 1 mixture of hexane, ethyl acetate.
1H NMR (CDCI3, 300 MHz) Γ r (ppm): 3.64 (s, 6H), 3.66 (s, 3H), 3.81 (s, 3H), 3.83 (s, 3H), 3.89 (s, 3H) 6.43 (s, 2H), 6.45 (s, 2H), 6.61 (d, / = 8.3 Hz, 1H), 6.79 (d, / = 8.3 Hz, 1H), 6.98 (t, / = 12.1, 8.98 Hz, 2H), 7.28(t, / = 12.1 Hz, 2H), 7.42 (d / = 2.26 Hz, NH), 7.61 (d, / = 8.87 Hz, 2H); FABMAS:(M+H)=515.
Example 3:
[018](Z)-4-chloro-N-(2-methoxy-5-(3,4,5-trimethoxystyryl)phenyl)benzenesulfonamide (12c):
To a solution of (Z)-4-methoxy-N-(2-methoxy-5-(3,4,5-trimethoxystyryl) aniline(100mg, leqt, 0.317 mmol) in a 1 :4 mixture of pyridine and anhydrous CH2CI2 (lOmL), 4-chloro benzenesulfonylchloride (81mg 0.380 mmol) was slowly added at 0°C. After 5 min stirring remove ice both and stirred at room temperature 2-3 h, then the reaction mixture was evaporated to dryness in vacuum and the residue was taken up with CH2C12 (10 mL). The organic solution was washed with water, 10%aqueous HCl, water and brine, dried over MgS04, and concentrated in vacuum to give 166 mg (93%) of analytically pure compound obtained from a 3 : 1 mixture of hexane, ethyl acetate.
1H NMR (CDC13, 300 MHz) Ί l(ppm): 3.64 (s, 3H), 3.68 (s, 6H), 3.84 (s, 3H), 3.83 (s, 3H) 6.44 (s, 2H), 6.46 (s, 2H), 6.61 (d, / = 8.3 Hz 1H), 6.93 (s, 1H), 6.98(d, / = 8.3 Hz, 1H), 7.02- 7.03 (m, 2H), 7.40 (d, / = 2.26Hz, NH), 7.65-7.70 (d, / = 12.1 Hz, 2H); FABMAS:(M+H)=489.
Example 4:
[019](Z)-N-(2,3-dimethoxy-5-(3,4,5-trimethoxystyryl)phenyl)-4-methoxybenzene sulfonamide (13a):
To a solution of (Z)-2,3-dimethoxy-5-(3,4,5-trimethoxystyryl)benzenamine (lOOmg, leqt, 0.289 mmol) in a 1:4 mixture of pyridine and anhydrous CH2CI2 (lOmL), 4-methoxy benzenesulfonyl chloride (71 mg, 0.347 mmol) was slowly added at 0 °C. After 5 min stirring remove ice both and stirred at room temperature 2-3 h, then the reaction mixture was evaporated to dryness in vacuum and the residue was taken up with CH2C12 (10 mL). The organic solution was washed with water, 10%aqueous HCl, water and brine, dried over MgS04, and concentrated in vacuum to give 153 mg (90%) of analytically pure compound obtained from a 3:1 mixture of hexane, ethyl acetate.
1H NMR (CDCI3, 300 MHz) I I I (ppm):3.72 (s, 9H), 3.87 (s, 3H), 3.92 (s, 3H), 4.05 (s, 3H), 5.90 (d, / = 7.55 Hz, 1H), 6.59(d, / =12.1 Hz, 5H) 6.8 (s, 1H), 7.24-7.17 (m, 1H) 7.37(s, 3H), 7.73(s, 1H), 8.5 (s, 1H), 12.01 (d, / =12.1 Hz, NH); FABMAS:(M+H)=515.
Example 5:
[020](Z)-N-(2,3-dimethoxy-5-(3,4,5-trimethoxystyryl)phenyl)-3,4-dimethoxybenzene sulfonamide (13b):
To a solution of (Z)-2,3-dimethoxy-5-(3,4,5-trimethoxystyryl)benzenamine (lOOmg, leqt, 0.289 mmol) in a 1:4 mixture of pyridine and anhydrous CH2CI2 (lOmL), 3,4- dimethoxybenzene sulfonyl chloride (82 mg, 0.347 mmol) was slowly added at 0 °C. After 5 min stirring remove ice both and stirred at room temperature 2-3 h, then the reaction mixture was evaporated to dryness in vacuum and the residue was taken up with CH2CI2 (10 mL). The organic solution was washed with water, 10% aqueous HCl, water and brine, dried over MgS04, and concentrated in vacuum to give 165 mg (92%) of analytically pure compound obtained from a 3: 1 mixture of hexane, ethyl acetate.
1H NMR (CDCI3, 300 MHz) 1 r(ppm): _ 3.72 (s, 6H), 3.82 (s, 3H), 3.84 (s, 3H), 3.90 (s, 3H), 3.94 (s, 3H), 3.96 (s, 3H), 5.93 (d, / = 12.1 Hz, 1H), 6.58 (s, 2H) 6.79 (d, / = 12.1 Hz, 1H), 7.19 (s, 1H) 7.23 (s, 1H), 6.70 (s, 1H), 6.73 (d, 1H), 6.82 (d,lH);FABMAS:(M+H)=545.
Example 6:
[021](Z)-4-chloro-N-(2,3-dimethoxy-5-(3,4,5- trimethoxystyryl)phenyl)benzenesulfonamide(13c):
To a solution of (Z)-2,3-dimethoxy-5-(3,4,5-trimethoxystyryl)benzenamine (100 mg, 0.289 mmol) in a 1 :4 mixture of pyridine and anhydrous CH2CI2 (lOmL), 4-chloro benzenesulfonyl chloride (73 mg, 0.347 mmol) was slowly added at 0 °C. After 5 min stirring remove ice both and stirred at room temperature 2-3 h, then the reaction mixture was evaporated to dryness in vacuum and the residue was taken up with CH2Cl2(10 mL). The organic solution was washed with water, 10% aqueous HCl, water and brine, dried over MgS0 , and concentrated in vacuum to give 157 mg (92%) of analytically pure compound obtained from a 3:1 mixture of hexane, ethyl acetate.
1H NMR (CDCI3, 300 MHz) _ _ (ppm): J J 3.72 (s, 6H), 3.83 (s, 3H), 3.90 (s, 3H), 3.95 (s, 3H), 5.96 (d, / = 12.1 Hz, 1H), 6.75 (s, 2H) 6.81 (d, / = 12.1 Hz, 1H), 7.06 (s, 1H), 7.23 (s, 1H), 7.34 (s, / = 7.4 Hz, 2H), 7.43 (s, / = 7.4 Hz, 2H); FABMAS:(M+H)=519.
Example 7:
[022](Z)-N-(2-hydroxy-3-methoxy-6-(3,4,5-trimethoxystyryl)phenyl)-4-methoxybenzene sulfonamide (17a):
To a solution of (Z)-2-(tert-butyldimethylsilyloxy)-3-methoxy-6-(3,4,5-trimethoxystyryl) benzenamine (100 mg, 0.302 mmol) in a 1 :4 mixture of pyridine and anhydrous CH2C12 (lOmL), 4-methoxybenzenesulfonyl chloride (74 mg 0.362 mmol) was slowly added at 0°C. After 5 min stirring remove ice both and stirred at room temperature 2-3 h, then the reaction mixture was evaporated to dryness in vacuum and the residue was taken up with CH2CI2 (10 mL). The organic solution was washed with water, 10% aqueous HCl, water and brine, dried over MgS04, and concentrated in vacuum to give 158 mg (91%) of analytically pure compound obtained from a 3: 1 mixture of hexane, ethyl acetate.
Example 8:
sulfonamide (17b):
To a solution of ((Z)-2-(tert-butyldimethylsilyloxy)-3-methoxy-6-(3,4,5-trimethoxystyryl) benzenamine (100 mg, leqt, 0.302 mmol) in a 1:4 mixture of pyridine and anhydrous CH2C12 (lOmL), 3,4-dimethoxybenzene sulfonyl chloride (85mg, 0.362 mmol) was slowly added at 0 °C. After 5 min stirring remove ice both and stirred at room temperature 2-3 h, then the reaction mixture was evaporated to dryness in vacuum and the residue was taken up with CH2CI2 (10 mL). The organic solution was washed with water, 10% aqueous HCl, water and brine, dried over MgSO4, and concentrated in vacuum to give 164 mg (90%) of analytically pure compound obtained from a 3: 1 mixture of hexane, ethyl acetate.
1H NMR (CDCI3, 300 MHz) I I (ppm): 3.61 (s, 6H), 3.76 (s, 3H), 3.81 (s, 3H), 3.86 (s, 3H), 3.91 (s, 3H),5.86 (d, / = 12.1 Hz 1H), 6.26 (d, / = 12.1 Hz 1H), 6.27 (s, 2H), 6.63 (s, 1H), 6.70 (dJ = 8.18HzlH), 6.73 (dJ = 8.23 Hz 1H), 6.82 (d, J = 8.45 Hz 1H), 7.12 (d, 1H), 7.63 (d,/ = 8.32 HzlH);FABMAS:(M+H)=531.57.
Example 9:
[024](Z)-4-chloro-N-(2-hydroxy-3-methoxy-6-(3,4,5- trimethoxystyryl)phenyl)benzenesulf onamide ( 17c) :
To a solution of (Z)-2-(tert-butyldimethylsilyloxy)-3-methoxy-6-(3,4,5-trimethoxystyryl) benzenamine (100 mg, 0.302 mmol) in a 1 :4 mixture of pyridine and anhydrous CH2CI2 (lOmL), 4-chloro benzenesulfonylchloride (76 mg, 0.362 mmol) was slowly added at 0°C. After 5 min stirring remove ice both and stirred at room temperature 2-3 h, then the reaction mixture was evaporated to dryness in vacuum and the residue was taken up with CH2CI2 (10 mL). The organic solution was washed with water, 10% aqueous HCl, water and brine, dried over MgS04, and concentrated in vacuum to give 160 mg (90%) of analytically pure compound obtained from a 3: 1 mixture of hexane, ethyl acetate. 1H NMR (CDCI3, 300 MHz) l (ppm): 3.63 (s, 6H), 3.82(s, 3H), 3.85 (s, 3H), 6.04(d, / = 12.1 Hz, 1H), 6.19 (s, H), 6.28 (d, / = 12.1 Hz, 1H), 6.31 (s, 2H), 6.72 (s, 2H), 7.35(dJ= 8.42 Hz 2H), 7.65 (s, 2H), ppm. FABMAS:(M+H)=505
Example 10:
[025](Z)-4-tert-butyl-N-(2-hydroxy-3-methoxy-6-(3,4,5- trimethoxystyryl)phenyl)benzenesulfonamide(17g):
To a solution of (Z)-2-(tert-butyldimethylsilyloxy)-3-methoxy-6-(3,4,5-trimethoxystyryl) benzenamine (100 mg, 0.302 rnmol) in a 1 :4 mixture of pyridine and anhydrous CH2CI2 (lOmL), 4-tert-butylbenzenesulfonyl chloride (85.5mg, 0.362 mmol) was slowly added at 0°C. After 5 min stirring remove ice both and stirred at room temperature 2-3 h, then the reaction mixture was evaporated to dryness in vacuum and the residue was taken up with CH2C12(10 mL). The organic solution was washed with water, 10%aqueous HCl, water and brine, dried over MgS04, and concentrated in vacuum to give 163mg (90%) of analytically pure compound obtained from a 3: 1 mixture of hexane, ethyl acetate.
1H NMR (CDCI3, 300 MHz) n (ppm): 1.30 (s, 9H) 3.62 (s, 6H), 3.81 (s, 3H), 3.87 (s, 3H), 5.76 (d, 7=11.9 1H), 6.22 (d, 7=11.897 1H), 6.26(s, 2H), 6.68(d,lH), 6.72(d, / = 8.26 Hz 1H), 7.40 (d, / = 8.49Hz, 2H),7.63 (d, /=8.498 Hz, 2H), ppm. FABMAS: (M+H)=527.
Anticancer activity: Some of invitro biological activity studies were carried out at the National Cancer Institute, Marryland, USA.
[026]/n vitro cytotoxicity: The (Z)-3,4,5-trimethoxystyryl benzene sulfonamides (13a,13c,17a,17c and 12a) have been tested against sixty human tumor cell lines derived from different type of nine cancer cell lines (leukemia, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer and breast cancer) as per the NCI protocol. For each compound, dose response curves for individual cell lines have been measured at a minimum of five concentrations at 10 fold dilutions. A protocol of 48 h continuous drug exposure has been used, and a sulforhodamine B (SRB) protein assay was used to estimate cell viability or growth. The concentration for50% cell growth inhibition (GI50), total cell growth inhibition (TGI, 0% growth) and 50% cell death (LC50, 50% growth) compared with the control has been calculated (Table- 1). The compounds 13a,13c,17a,17c and 12a has been evaluated for their in vitro cytotoxicity in sixty cell lines from nine human cancer types of leukemia (K-562, SR), lung (Hop-62, NCI-H226, NCI-H522), colon (HCT-116, HCT- 15, HCC-2998), CNS (SF-539), melanoma (SK-MEL-5, UACC-62, M14), ovarian (IGROV1), renal (A498), prostate (PC3) breast (BT-549, MDA-MB-435, HS578T)origin. The results are expressed as percent of cell growth determined relative to that of untreated control cells (Table 2). The representative compounds 13a, 13c, 17a, 17c and 12a showed significant cytotoxicity against almost 50 above cancer cell lines.
[027]The compounds 17a,17c,13a,13c and 12a exhibited a wide spectrum of activity against fifty six cell lines in nine different types of cancer cell lines, most of the compounds with GI50 value range of 18-50nM. Particularly, the compounds 13a, 17a, and 12a were more potent than the compoundsl3candl7cagainst all the tested cell lines. The GI50 values for the compound 17a and 13a against almost all tumor cell lines below 50nM,in that eight types of different tumor cell lines shows below 30nM and below 40nm shows by twenty five cell lines and around forty above cell lines shows with GI50 values below 50nM. 17c and 12a also shows good GI50 values below 30nm around eight tumor cell lines, with GI50 values below 50nm shows by thirty above cell lines. In detailjn the non-small cell lung cancer panel, the growth of NCI-H522 cell line were affected by compound 17awith GI50 values as 20.2nM. The GI50 values for the compound 13a against non-small lung cancer cell line NCI-H522 19.7nM.Whereas the colon cancer cell line colo-205 affected by compound 13a with GI50 value of 21.4 nM. The GI50 values for compounds 17a, 17c, 13a and 12a againstrenal A498 cell line were 18.8, 22.9, 21.7 and 35.3 nM respectively. In the leukemia cancer panel the cell lines CCRF-CEM, HL-60(TB),SR and K-562 were affected by 17a with GI50 value 30.1, 23.5,31.9 and 28.6 nM and 13a with GI50 values 32.9,23.4,35.2 and 27.2 respectively, and The GI50 values for compounds 17a,17c and 13a againstmelanoma MDA-MB-435 cell line were 19.0,22.2 and 21.1 nM, respectively. In the CNS cancer panel the cell lines SF-295,SF-539,U251 and SNB75 were affected by 17a with GI50 values 33.9, 29.3,37.4 and 25.5 nM and 13a with GI50 values 31.1,25.3,35.7 and 26.5 respectively, the GI50 values for the compound 12a against melanoma cancer cell line MDA- MB-435is 27.4 nM. In the non-small cell lung cancer panel, the growth of HOP-62 and NCI- H522 cell lines were affected by compound 12awith GI50 values as 41 and 20.4 nM, respectively. Whereas in the breast cancer cell line MCF-7, the growth was affected by 12a with GI50 value 42.6 nM. The GI50 values for the compounds 17a, 13a and 12a against Non- small cell lungcancer cell line NCI-H522 is 20.2,19.7 and 20.4nM respectively. The GI50 values for compounds 17a,17c,13a and 12aagainst melanoma cell line MDA-MB-435 were 19.2,22.2,21.1 and 27.4 nM respectively. The GI50 values for the compound 12aagainst renal cancer cell line A498 were 35.3nM. Overall, the growth affected by the compounds 17a, 17c, 13a and 12a against all the cancer cell lines with GI50 values range 18-50 nM.
[028]Compounds 17a, 17c, 13a, 13c and 12a exhibited activity against fifty eight cell lines in nine cancer cell panels with GI50 values of 20nM to 50nm.Invitro cytotoxicity of compounds 17a, 17c,13a,13c and 12a in the selected cancer cell lines has been illustrated in Table 1.
Table l.In vitro cytotoxicity of compounds 17a,17c,13a,13c and 12a in a panel of 60 human cancer cell lines.
NT=NotTested.
[029]The mean graph midpoint values of Log10 TGI and Log10 LC50 as well as Log10 GI50 for compounds 17a,17c, 13a,13cand 12a is listed in Table-2. As demonstrated by mean graph pattern, compoundsl7a,17c,13a,13c and 12a exhibited an interesting profile of activity and selectivity for various cell lines. The mean graph midpoints of Log10 TGI and Log10 LC50 have shown similar pattern to the log10 GI50 mean graph mid points.
Table 2. Log10 GI50, Log10 TGI and Log10 LC50 mean graphs mid points(MG_MID) of in vitro cytotoxicity data for the compoundl7a,17c,13a,13c and 12a against human tumor cell lines.
[026]AD VANTAGES OF THE PRESENT INVENTION
1. The present invention provides new (Z)-3,4,5-trimethoxystyrylbenzenesulfonamides that may be useful as antitumor agents.
2. It also provides a process for the preparation of (Z)-3,4,5- trimethoxystyrylbenzenesulfonamides.
3. Some new (Z)-3,4,5-trimethoxystyrylbenzenesulfonamides that have been synthesized exhibited significant cytotoxic activity against sixty human cancer cell lines.

Claims

WE CLAIM
1. A (Z)-3,4,5-trimethoxystyryl benzene sulfonamides of general formula A
wherein, X= H, F, OCH3, NH2, OH; R = H, CI, F, OCH3, NH2, N02, OH
(Z)-3,4,5-trimethoxystyryl benzenesulfonamides as claimed in claim 1 wherein the 3,4,5-trimethoxystyrylbenzenesulfonamide derivatives of formula A is represented by the compounds of general formulae9a-9y, lOa-lOy, lla-lly, 12a-12y, 13a-13y, 14a- 14y, 15a-15y, 16a-16y, 17a-17y, 18a-18y, 19a-19y, 20a-20y, 21a-21y,22a-22yand 23a-23y,
wherein R = H, CI, F, OCH3, NH2, N02, OH.
3. The compound as claimed in claim 1, wherein the representative compounds of (Z)- trimethoxystyryl)phenyl) benzene sulfonamide comprising:
3. (Z)- 3,4,5-trimethoxystyrylbenzenesulfonamides as claimed in claim 1 wherein the structural formulae of the representative compounds are:
wherein R = H, CI, F, OCH3, NH2, N02, OH.
4. The compound as claimed in clam 1, wherein the compound of general formula A are useful as antitumor agents.
5. The compound as claimed in clam 1, wherein the compound of general formula A have antitumour activity against cell lines selected from the group consisting of non-small cell lung cancer, colon cancer, cervical carcinoma and breast cancer.
EP15808035.8A 2014-10-29 2015-10-27 (z)-3,4,5-trimethoxystyrylbenzenesulfonamides as potential anticancer agents Active EP3212613B1 (en)

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